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PubMed2006

Origins and impact of constraints in evolution of gene families.

Recent investigations of high-throughput genomic and phenomic data have uncovered a variety of significant but relatively weak correlations between a gene's functional and evolutionary characteristics. In particular, essential genes and genes with paralogs have a slight propensity to evolve more slowly than nonessential genes and singletons, respectively. However, given the weakness and multiplicity of these associations, their biological relevance remains uncertain. Here, we show that existence of an essential paralog can be used as a specific and strong gauge of selection. We partition gene families in several genomes into two classes: those that include at least one essential gene (E-families) and those without essential genes (N-families). We find that weaker purifying selection causes N-families to evolve in a more dynamic regime with higher rates both of duplicate fixation and pseudogenization. Because genes in E-families are subject to significantly stronger purifying selection than those in N-families, they survive longer and exhibit greater sequence divergence. Longer average survival time also allows for divergence of upstream regulatory regions, resulting in change of transcriptional context among paralogs in E-families. These findings are compatible with differential division of ancestral functions (subfunctionalization) or emergence of novel functions (neofunctionalization) being the prevalent modes of evolution of paralogs in E-families as opposed to pseudogenization (nonfunctionalization), which is the typical fate of paralogs in N-families. Unlike other characteristics of genes, such as essentiality, existence of paralogs, or expression level, membership in an E-family or an N-family strongly correlates with the level of selection and appears to be a major determinant of a gene's evolutionary fate.

Animals↗
PubMed2004

[Redeployment of the Six genes in evolution].

It has become clear that during evolution, efficient molecular mechanisms are used over and over again to achieve various patterning tasks. The Six gene story illustrates a new aspect of the molecular conservation during embryogenesis. Members of the Six gene family have been identified on the basis of sequence homology with Drosophila sine oculis gene, which acts within a network of genes including eyeless (Pax family), eyes absent (Eya family) and dachshund (Dach family) to trigger compound eye organogenesis. Some aspects of the regulatory complex operating in Drosophila appear to be conserved during vertebrate eye patterning, but also for other differentiation processes. In this regard, Six1 is required nonetheless during myogenesis, but also for kidney, thymus, inner ear, nose, lacrimal and salivary gland organogenesis. These phenotypes are reminiscent of those previously described for Eya and Pax mutants, suggesting a functional link between these factors during mammalian organogenesis.

Animals↗
PubMed2004

Gene regulatory network growth by duplication.

We are beginning to elucidate transcriptional regulatory networks on a large scale and to understand some of the structural principles of these networks, but the evolutionary mechanisms that form these networks are still mostly unknown. Here we investigate the role of gene duplication in network evolution. Gene duplication is the driving force for creating new genes in genomes: at least 50% of prokaryotic genes and over 90% of eukaryotic genes are products of gene duplication. The transcriptional interactions in regulatory networks consist of multiple components, and duplication processes that generate new interactions would need to be more complex. We define possible duplication scenarios and show that they formed the regulatory networks of the prokaryote Escherichia coli and the eukaryote Saccharomyces cerevisiae. Gene duplication has had a key role in network evolution: more than one-third of known regulatory interactions were inherited from the ancestral transcription factor or target gene after duplication, and roughly one-half of the interactions were gained during divergence after duplication. In addition, we conclude that evolution has been incremental, rather than making entire regulatory circuits or motifs by duplication with inheritance of interactions.

Bacterial Proteins↗
PubMed1990

Chimeric phage-bacterial enzymes: a clue to the modular evolution of genes.

Pneumococcal peptidoglycan amidase (N-acetylmuramoyl-L-alanine amidase, EC 3.5.1.28) and phage CPL1 lysozyme degrade a common substrate (choline-containing pneumococcal cell walls); the former hydrolyzes the bond between muramic acid and alanine, whereas the latter breaks down the linkage between muramic acid and glucosamine. The amino acid sequences of their C-terminal domains are homologous. Chimeric genes were constructed by site-directed mutagenesis: a unique SnaBI restriction site in the cpl1 gene, coding for the phage lysozyme, was introduced at a location equivalent to the SnaBI site present in the lytA gene, which codes for the pneumococcal amidase. The resulting genes expressed lytic activities at levels similar to those of the parental genes. The gene products, which have been purified to electrophoretical homogeneity, exhibited unusual combined biochemical properties--e.g., by exchange of protein domains, we have switched the regulatory properties of these enzymes without altering their catalytic activities. Chimeric gene construction in Streptococcus pneumoniae and its bacteriophages is an excellent model to study the modular organization of genes and proteins and to help to establish evolutionary relationships between phage and bacteria. These constructions provide an experimental approach to the molecular processes involved in cassette recruitment during evolution and contribute support to the concept of bacteria as adaptable chimeras.

Amino Acid Sequence↗
PubMed1992

Fractal landscapes in biological systems: long-range correlations in DNA and interbeat heart intervals.

Here we discuss recent advances in applying ideas of fractals and disordered systems to two topics of biological interest, both topics having common the appearance of scale-free phenomena, i.e., correlations that have no characteristic length scale, typically exhibited by physical systems near a critical point and dynamical systems far from equilibrium. (i) DNA nucleotide sequences have traditionally been analyzed using models which incorporate the possibility of short-range nucleotide correlations. We found, instead, a remarkably long-range power law correlation. We found such long-range correlations in intron-containing genes and in non-transcribed regulatory DNA sequences as well as intragenomic DNA, but not in cDNA sequences or intron-less genes. We also found that the myosin heavy chain family gene evolution increases the fractal complexity of the DNA landscapes, consistent with the intron-late hypothesis of gene evolution. (ii) The healthy heartbeat is traditionally thought to be regulated according to the classical principle of homeostasis, whereby physiologic systems operate to reduce variability and achieve an equilibrium-like state. We found, however, that under normal conditions, beat-to-beat fluctuations in heart rate display long-range power law correlations.

Animals↗
PubMedDate not supplied

Otx genes in evolution: are they involved in instructing the vertebrate brain morphology?

Previous mouse models have indicated that Otx1 and Otx2 play an important role in brain and sense organ development and, together with the Drosophila orthodenticle (otd) gene, they share a high degree of reciprocal functional equivalence. Interestingly, mouse models replacing the same region of the Otx2 locus with Otx1, otd or lacZ genes have revealed the existence of a differential post-transcriptional control between the visceral endoderm (VE) and epiblast cells. Indeed Otx1, otd or lacZ mRNA were transcribed in both tissues but translated only in the VE. Embryos lacking OTX1 or OTD proteins in the epiblast and derived tissues, such as the neuroectoderm and axial mesendoderm (AME), fail to maintain the anterior identity and result in a headless phenotype. This finding leads us to hypothesise that, during evolution, the specification of the vertebrate-type brain may have required epiblast cells to translate Otx2 mRNA in order to establish maintenance properties. The establishment of this regulatory control might have been reflected into a remarkable reorganisation of the rostral CNS architecture and might have represented an important event in the evolution of the vertebrate head. Current data suggest that the Otx2 replaced region and in particular the 3' untranslated region (UTR), may contain regulatory element(s) necessary to translate and/or stabilise Otx2 mRNA in epiblast and its derivatives.

3' Untranslated Regions↗
PubMed2000

Evolution: hox genes and the cellared wine principle.

Two Drosophila Hox genes involved in segmentation, fushi tarazu and bicoid, appear to have acquired these roles by functional divergence from classical homeotic genes. Recent results indicate how genes with critical functions in development can evolve completely different functions among species.

Animals↗
PubMed1989

Evidence that introns arose at proto-splice sites.

The unexpected discovery of introns raised many questions about gene evolution. We provide evidence that actin and tubulin introns were gained between the G and R of the conserved coding sequence C/AAGR that is known to flank introns in general and which we call a proto-splice site. We conclude that the tubulin and actin introns are less ancient than the coding sequence and so could not have been involved in the primary evolution of the tubulin and actin genes.

Actins↗
PubMed1997

The evolution of gene expression, structure and function of transthyretin.

Thyroxine, the most abundant thyroid hormone in blood, partitions into lipid membranes. In a network-like system, thyroxine-binding plasma proteins counteract this partitioning and establish intravascular, protein-bound thyroxine pools. These are far larger than the free thyroxine pools. In larger eutherians, proteins specifically binding thyroxine are albumin, transthyretin, and thyroxine-binding globulin. Some binding of thyroxine can also occur to lipoproteins. During evolution, transthyretin synthesis first appeared in the choroid plexus of the stem reptiles, about 300 million years ago. Transthretin synthesis in the liver evolved much later, independently, in birds, eutherians and some marsupial species. Analysis of 57 human transthyretin variants suggests that most mutations in transthyretin are not compatible with its normal metabolism and lead to its deposition as amyloid. Analysis of transthyretin or its gene in 20 different species shows that evolutionary changes of transthyretin predominantly occurred near the N-termini. A change in RNA splicing between exon 1 and exon 2 led to a decrease in hydrophobicity and length of the N-termini. It is proposed that the selection pressure producing these changes was the need for a more effective prevention of thyroxine partitioning into lipids. Lipid pools increased during evolution with the increases in relative sizes of brains and internal organs and changes in lipid composition of membranes in ectothermic and endothermic species.

Amino Acid Sequence↗
PubMed1995

Structure and evolution of genes encoding polyubiquitin and ubiquitin-like proteins in Arabidopsis thaliana ecotype Columbia.

The Arabidopsis thaliana ecotype Columbia ubiquitin gene family consists of 14 members that can be divided into three types of ubiquitin genes; polyubiquitin genes, ubiquitin-like genes and ubiquitin extension genes. The isolation and characterization of eight ubiquitin sequences, consisting of four polyubiquitin genes and four ubiquitin-like genes, are described here, and their relationships to each other and to previously identified Arabidopsis ubiquitin genes were analyzed. The polyubiquitin genes, UBQ3, UBQ10, UBQ11 and UBQ14, contain tandem repeats of the 228-bp ubiquitin coding region. Together with a previously described polyubiquitin gene, UBQ4, they differ in synonymous substitutions, number of ubiquitin coding regions, number and nature of nonubiquitin C-terminal amino acid(s) and chromosomal location, dividing into two subtypes; the UBQ3/UBQ4 and UBQ10/UBQ11/UBQ14 subtypes. Ubiquitin-like genes, UBQ7, UBQ8, UBQ9 and UBQ12, also contain tandem repeats of the ubiquitin coding region, but at least one repeat per gene encodes a protein with amino acid substitutions. Nucleotide comparisons, Ks value determinations and neighbor-joining analyses were employed to determine intra- and intergenic relationships. In general, the rate of synonymous substitution is too high to discern related repeats. Specific exceptions provide insight into gene relationships. The observed nucleotide relationships are consistent with previously described models involving gene duplications followed by both unequal crossing-over and gene conversion events.

Amino Acid Sequence↗
PubMed1995

Genetic analysis of cinnamyl alcohol dehydrogenase in loblolly pine: single gene inheritance, molecular characterization and evolution.

The gene encoding the monolignol biosynthetic enzyme cinnamyl alcohol dehydrogenase (CAD, E.C. 1.1.1.195) can be expressed in response to different developmental and environmental cues. Control of Cad gene expression could involve either differential regulation of more than one Cad gene or, alternatively combinatorial regulation of a single Cad gene. In loblolly pine (Pinus taeda L.), we found several electrophoretic variants (allozymes) of CAD and a high level of heterozygosity (he = 0.46). Analysis of inheritance patterns of pine CAD allozymes gave segregation ratios that were consistent with Mendelian expectations for a single functional gene. The identity of the full-length Cad cDNA sequence was confirmed by alignment with peptide sequences obtained from purified active enzyme and by extensive similarity to Cad sequences from other species. Southern blot analysis of genomic DNA using the Cad cDNA as a hybridization probe gave simple patterns, consistent with our interpretation that pine Cad is a single-copy gene. Phylogenetic analysis and evolution rate estimates showed that Cad sequences are diverging less rapidly in the gymnosperms than in the angiosperms. The Cad mRNA was present in both lignifying tissues and a non lignifying tissue (the megagametophyte) of pine. The presence of a single gene suggests that different regulatory mechanisms for a single Cad gene, rather than differential regulation of several genes, can account for its expression in response to different cues.

Alcohol Oxidoreductases↗
PubMed1988

The molecular evolution of genes and proteins: a tale of two serines.

The advent of techniques for cloning and rapidly sequencing DNA has produced an explosive increase of sequence information for nucleic acids and their inferred proteins. Careful study of this large store of data might give us new insights into the relations between the linear sequences of genes and their functions embodied in the three-dimensional structure of proteins, and also illuminate the origin and evolution of the structural complexity of present-day proteins. Here I argue from such a study that the active site sequences of enzymes that have analogous essential serine residues lie in fact on two lines of descent from an ancient ancestral enzyme which had a cysteine instead of serine in its active site. This is based on the assumption that the two codon types which define the separate lines of descent and which have different bases in two positions could not interconvert by single mutations.

Amino Acid Sequence↗
PubMed2002

Structure, molecular evolution, and gene expression of primate superoxide dismutases.

Mn- and Cu,Zn-superoxide dismutase (SOD) cDNAs of eight primate species, Pan troglodytes, Pongo pygmaeus, Hylobates lar, Macaca fuscata, Macaca fascicularis, Macaca mulatta, Cebus apella, and Callithrix jacchus, were cloned. The whole protein-coding sequences were covered, comparing 198 and 153 (or 154) amino acids, for Mn- and Cu,Zn-SODs, respectively. Residues forming metal ligands were completely conserved in the two primate SODs and nucleotide/amino acid substitutions were more frequent in Cu,Zn-SODs than in Mn-SODs. Molecular evolutionary analyses showed Mn-SOD to have evolved at a constant rate and its phylogenetic tree well reflected primate phylogeny. Cu,Zn-SOD was shown to have evolved differently between primate lineages. The significant high ratio of a non-synonymous/synonymous rate was found in the lineage leading to great apes and humans, showing that this lineage underwent positive Darwinian selection. Southern hybridization suggested that the genes for primate Mn- and Cu,Zn-SOD exist as single copies. Northern analysis in various Japanese monkey tissues showed Mn- and Cu,Zn-SOD expression to be high in the liver, kidneys, and adrenal glands.

Amino Acid Sequence↗
PubMed2002

Novel PAX6 binding sites in the human genome and the role of repetitive elements in the evolution of gene regulation.

Pax6 is a critical transcription factor in the development of the eye, pancreas, and central nervous system. It is composed of two DNA-binding domains, the paired domain (PD), which has two helix-turn-helix (HTH) motifs, and the homeodomain (HD), made up from another HTH motif. Each HTH motif can bind to DNA separately or in combination with the others. We identified three novel binding sites that are specific for the PD and HD domains of human PAX6 from single-copy human genomic DNA libraries using cyclic amplification of protein binding sequences (CAPBS) and electrophoretic mobility shift assays (EMSAs). One of the binding sites was found within sequences of repetitive Alu elements. However, most of the Alu sequences were unable to bind to PAX6 because of a small number of mismatches (mostly in CpG dinucleotide hot spots) in the consensus Alu sequences. PAX6 binding Alu elements are found primarily in old and intermediate-aged Alu subfamilies. These data along with our previously identified B1-type Pax6 binding site showed that evolutionarily conserved Pax6 has target sites that are disparate in primates and rodents. This difference indicates that human and mouse Pax6-regulated gene networks may have evolved through these lineage-specific repeat elements.

Alu Elements↗
PubMed1989

DNA microenvironments and the molecular clock.

A few years ago we presented a stationary Markov model of gene evolution according to which only homologous genes from not too divergent species obeying the condition of being stationary may behave as reliable molecular clocks. A compartmentalized model of the nuclear genome in which the genes are distributed in compartments, the isochores, defined by their G + C content has been proposed recently. We have found that only homologous gene pairs that are stationary, and belong to the same isochore, can be used consistently for the determination of phylogeny and base substitution rate. In particular, for the rodent-human couple, only about half of the homologous gene pairs are stationary. Stationary genes evolve at the third silent codon position with the same velocity independent of the genes and base composition. By contrast, nonstationary genes display apparent rate values (pseudovelocities) that are significantly higher. Our results cast doubt upon recent claims of a large acceleration in the rate of molecular evolution in rodents.

Biological Evolution↗
PubMed1994

Canavan disease: genomic organization and localization of human ASPA to 17p13-ter and conservation of the ASPA gene during evolution.

Canavan disease, or spongy degeneration of the brain, is a severe leukodystrophy caused by the deficiency of aspartoacylase (ASPA). Recently, a missense mutation was identified in human ASPA coding sequence from patients with Canavan disease. The human ASPA gene has been cloned and found to span 29 kb of the genome. Human aspartoacylase is coded by six exons intervened by five introns. The exons vary from 94 (exon III) to 514 (exon VI) bases. The exon/intron splice junction sites follow the gt/ag consensus sequence rule. Southern blot analysis of genomic DNA from human/mouse somatic cell hybrid cell lines localized ASPA to human chromosome 17. The human ASPA locus was further mapped in the 17p13-ter region by fluorescence in situ hybridization. The bovine aspa gene has also been cloned, and its exon/intron organization is identical to that of the human gene. The 500-base sequence upstream of the initiator ATG codon in the human gene and that in the bovine gene are 77% identical. Human ASPA coding sequences cross-hybridize with genomic DNA from yeast, chicken, rabbit, cow, dog, mouse, rat, and monkey. The specificity of cross-species hybridization of coding sequences suggests that aspartoacylase has been conserved during evolution. It should now be possible to identify mutations in the noncoding genomic sequences that lead to Canavan disease and to study the regulation of ASPA.

Amidohydrolases↗